JPS606646A - 1,3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate, manufacture and medicinal composition - Google Patents

Abstract

This invention relates to the new 1,3-bis-(dimethylamino)-2-propyl-4-chlorophenoxyacetate of the Formula (I) <IMAGE> (I) acid addition salts thereof, a process for the preparation of the same and pharmaceutical compositions comprising the said compounds. The novel compound of the present invention corresponds to the Formula (I). This compound stimulates the function of the brain cells and thereby mental activity. The compound of the Formula (I) can be prepared by esterifying (4-chlorophenoxy)-acetic acid or a functional reactive derivative thereof with 1,3-bis-(dimethylamino)-2-propanol or a halogeno derivative thereof in a manner known per se.

Description

Detailed Description of the Invention Technical Field The present invention relates to a novel 1,5-bis(dimethylamino)-
The present invention relates to 2-propyl-4-chlorophenoxyacetate, acid addition salts thereof, processes for preparing these compounds, and pharmaceutical compositions comprising these compounds.

The compound represented by formula (1) and its acid addition salt are:
It is active as a neurostimulant and can prevent loss of brain function due to aging.

PRIOR ART It is known that dimethylaminoethyl-4-chlorophenoxyacetate exhibits memory and learning stimulating effects as well as neural activation effects (Martin Negwer ``
Organischchemische Arznei
-mittel und 1hre 8ynonym
aJ Akademie-Verlag, Hertz y,
1951 (1978)).

The above compound [Centrophenoxidine (Centroph)]
Pharmaceutical compositions comprising e-noxin) have been used therapeutically as central stimulants (Arzneimi et al.
ttelForschung'1! +, 881 (196
5)). Several methods are known for preparing the above compounds.

Most of these methods are esterification methods known per se [Czechoslovakia Patent No. 154,866, Japanese Patent Application Laid-open No. 47-389586, British Patent No. 95]
4.196, German Patent Publication No. 2, 006.35
Specification No. 8]. According to JP-A-50-19542, the resulting ester is subsequently chlorinated. Tokukai 1975
In Publication No. 19542, the desired compound a11#! is produced by reacting with three components, namely 4-chlorophenol, chloroacetic acid, and 1,2-bis(dimethylamino)ethanol. You can also.

In studies of the mechanism of action of the compounds, it has been found that the compounds, originally known as neurostimulants, also act on the aging process of cells. Chronic treatment of old animals with pre-dC compounds reduces the content of age-related pigments in brain neurons and myocardium [Nature, 210. +13(
(1966) 1. The lifespan of animals has increased appreciably,
Also, the learning ability of older animals improves (Exp
l, Gerontol, 8°185 (1975b))
I know that.

According to the cellular aging hypothesis, which interprets the aging process described above using a membrane-related theory, the first stage of aging, in which cells die after division, is due to the release of active free radicals generated during cellular respiration. The problem lies in the reduced permeability of immobile potassium in the cell membrane, probably as a result of its cross-linking capacity (J, The
or, Biol, 75, 189 (1978): Mec.
ll, Age, Dev, Mu 237 (1979):].

The substituted amino group of the above-mentioned known compound is
- Significant radical oxidation, possibly associated with
The effect is shown in vitro (Me c h , Aga
Dev, 14, 245 (1980)).

Nitrogen-containing esters of 4-chlorotetraphenoxyacetic acid known in the prior art, namely centrophenokidine, are
(Bull, Soc,
Chim, 1i'rance 1960, 1786:D
iol, Aktjv 5oedin 1965, 112
: C, A, 65゜■-Adjusted■■---i----
■■Hibiki 179480 (1965)).

OBJECTS AND STRUCTURE OF THE INVENTION The present invention is based on the recognition that the dimethylaminoethanol portion of the centrophenoquidine molecule enters brain tissue and neutralizes free radicals. Two amino groups are more active than one amine group, and by synthesizing similar compounds containing two substituted amine groups, we have found that they are more effective against the aging process of cells. It can be considered that effective therapeutic agents can be obtained.

According to the present invention, a novel compound represented by the formula (1), that is, 1,3-bis(dimethylaξ)]-]2-
Propyl-4-chlorophenoxy acetate and acid addition salts thereof are provided.

Furthermore, according to the present invention, the general formula (10 (wherein B1 is a carboxyl group, a cyano group, an alkoxycarbonyl group, a Hasekenocarbonyl group, a 4-chlorophenoxyacetoxycarbonyl group, or a general formula -〇〇〇M
A compound represented by a group represented by e', Me' is an alkali metal or ammonium ion) and a compound represented by the general formula (wherein R is a hydroxy group or an atom) 1 and optionally,
A method for producing the compound represented by formula (1) and its acid addition salt, which comprises separating the obtained compound represented by formula (1) from the reaction mixture in the form of an acid addition salt, preferably in the form of a hydrochloride. provided.

Detailed Description of the Structure and Effects of the Invention The esterification reaction in the method of the present invention can be carried out by a commonly used method known per se [8, Pate'rThe Cbetnistryo
f Carbox'ylic Ac1ds and h
starsJ'%IVley, London (1969)
], thus, for example, before i4e 6 formula (R in IQ
A free carboxylic acid when 1 is a carboxyl group and an alcohol or its/logogenated derivative when R2 is a hydroxy group or a )-logen atom in the general formula θF are reacted in a solvent. The above-mentioned free acids may include their functional derivatives, such as the corresponding dioxygenates (R is a -cyano group), anhydrides (R is a 4-chlorophenoxyacetoxycarbonyl group), and SO genides (R is a halogenated carbonyl group). ), or an ester (alkoxycarbonyl group).

A preferred embodiment is to use 4-chlorophenolic diacetyl chloride or nitrile as the acid component, carry out the reaction at elevated temperature in an organic solvent (benzene or xylene) as a medium, and to react with a compound represented by the general formula (ll[). In this case, 1,5-bis(dimethylamino)-2-propanonyl is used.

The above reaction can be carried out at 60-80°C for 2-3 hours. The reaction product d1 can be separated from the counterreactant, preferably in the form of the hydrochloride.

The acute toxicity of the novel compound according to the present invention was tested in male Alpino (white) CFLP rats by intraperitoneal and oral administration.

The toxicity data obtained by the Litchfield-Wilcoxon method are as follows.

LD (intraperitoneal) near 00±42■/KP0 LD (oral): 2540±300■false 0 Tests were also conducted on the effect of the novel compound represented by the formula (I) on lifespan. The active ingredient was dissolved in a sodium chloride physiological solution and administered intraperitoneally to five CFY rats at a daily dose of 100 kg. The average lifespan of the rats is approximately 5 months longer on average than that of the control rats.

The effects of the novel compound according to the present invention on biological membranes, particularly the cerebral cortex, were examined. In old age, the microviscosity of synaptosome membranes isolated from the cerebral cortex was found to increase significantly (the microviscosity was determined by measuring the anisotropic fluorescence of membranes marked with diphenylhexatriene). ). CFY rats aged 24 months were administered 1i101]y/II (intraperitoneally)'-c20.
The cells were treated with the active ingredient for days. As a result of this treatment, the above-mentioned parameters were improved. This result shows that
The results were almost the same as those measured on rats in 2007. This result is completely consistent with an increase in average lifespan.

The novel compound according to the present invention has no effect on NS synthesis in brain cells. The total and mRNS synthesis rates of cerebral cortical cells in old (24 months) rats are approximately half as low as in young and adult animals. Aged animals were treated with the active ingredient (daily dose 1001 N?/? i.p.) for 4 days.
Weekly treatment significantly promoted the synthesis of both fractions of N8, and the rate increased to almost the same level as that of 1-year-old animals.

Based on the above data, the novel compounds according to the invention are:
stimulates the functioning of brain cells, thereby reducing mental activity (consisting of association and learning abilities), especially when said mental activity is reduced as a result of natural aging or organ disease, traumatic conditions or coma; It can be expected to be stimulating. Therefore, the novel compounds of the present invention and their acid addition salts are: 1. It is useful as a neurostimulant or as a prophylactic agent to prevent age-related functional or brain damage (ie, an "anti-aging agent").

The effective amount of the novel compound represented by formula (1) according to the present invention is 1.1 to 500 mg/K for mammals.
g Preferably 20WT9/Up ~140++y/1z
It is.

The present invention further provides novel 1. −
A pharmaceutical composition comprising 3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate or a pharmaceutically acceptable acid addition salt thereof as the active ingredient in admixture with a suitable inert pharmaceutical carrier. It is also about providing things. The pharmaceutical composition of the present invention can be administered in the form of a tablet suitable for oral administration, and may contain conventional pharmaceutical carriers, auxiliaries or additives (for example, tar, starch, cellulose, etc.). Become.

Pharmaceutical compositions suitable for oral administration may also be capsules or coated formulations. Pharmaceutical compositions suitable for intravenous administration can be prepared by dissolving the active ingredient in water, physiological sodium chloride solution, or physiologically acceptable organic solvents such as various glycols. Pharmaceutical compositions suitable for intramuscular administration can be prepared by dissolving or suspending the active ingredient in the solvent. Solid compositions generally contain 20-90% active ingredient.
%, while the active ingredient content in solution or suspension is 1-10% and 1-70%, respectively.

EXAMPLES Hereinafter, the present invention will be explained in more detail based on Examples, but the scope of the present invention is not limited to the Examples.

Example 1 4-chlorophenoxyacetyl chloride 15. Or (
063 mol) was dissolved in 140 mol of benzene. After cooling the solution to 0°C, 1,6-bis(dimethylamino)-2-propatol 1a52r (126 moles of o) was added dropwise at such a rate that the temperature did not exceed 10°C. After the addition was complete, the reaction mixture was refluxed for 3 hours and the solvent was distilled off under vacuum. Dissolving the residual 1,3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate in a 10:1 mixture of diethyl ether and acetone and introducing gaseous hydrogen chloride into this mixture. The hydrochloride salt was precipitated by The precipitated crude product was separated, washed with ether and recrystallized from isopropanol. yield:
21.0f (85,59A).

Melting point: 210-212°C.

Elemental analysis: C15H25CtN203・2HCt (38
7,7) Calculated value: C46,46,H/), 50. N
7.22. C127,45% Actual value: C45,4
2, H6, 56, H7, 70, CL i26 λmax
(Methanol) 276nm Iogg: 1.5104I
R (KBr): 2580 (amine salt), 1765 (-
T-ster-carbonyl), 1215.1080 (aryl 7 alkyl maether), 820 (aromatic group at p position) cWrl 'H-NMR, (DM80): δZ23-Z17 (m,
aromatic), 5.71 (s, CH), 5.20 (s,
0-CH2), A47 (s, CH2), 2.
90 (s, CH3).

Example 2 4-chlorophenoxyacetyl chloride 6.5f (CJ
, 032 mol) was dissolved in 120-mol of toluene. This solution was cooled to 0°C, and 1,3-bis(dimethylamine)-2-propatol 942 (0,064 mol) was added to
It was added dropwise at a temperature below 0°C. The reaction mixture was heated to 80-8
After standing at 2° C. for 5 hours and cooling to room temperature, the hydrochloride of 1,3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate was precipitated by introducing gaseous hydrogen chloride. The crude product was taken from house to house, washed with isopropanol, and recrystallized from isopropanol. Yield: 10.1F (82.2%). Melting point: 209-211
℃. The other physical values of this product were the same as mentioned in Example 1.

Example 5 4-chlorophenoxyacetic anhydride6. Of (0,0
17 mol) was dissolved in benzene 70-, and 1,5-bis(dimethylamino)-2-7"lono(nol 5.6?(
0,019 mol) was added dropwise with stirring at 5-10°C. The reaction mixture was boiled for 8 hours and the solvent was distilled off under vacuum. The residual liquid 1,5-bis(dimethylamino)-
2-7' lobi-4-chlorophenoxy acetate,
The hydrochloride salt was precipitated by gaseous hydrogen chloride dissolved in a 10:1 mixture of diethyl ether and acetone. The crude product was recrystallized from isopropanol in a separate furnace. Yield: 5.7t (8102%). Melting point: 209-211°C.

The other physical values of this product corresponded to those described in Example 1.

Example 4 4-chlorophenoxyacetonitrile 15. Of(0,
085 mol) was dissolved in 80 m/ml of toluene.

To this solution was added 14.7 f (0.1 mol) of 1,5-bis(dimethylamine)=2-propanol and 2.0 f of 85% sulfuric acid at 5-10°C. 4-5 times the reaction mixture
Boiled for an hour, cooled to room temperature and neutralized with sodium carbonate solution. The neutral phase was washed with water, dried and gaseous hydrogen chloride was introduced to precipitate the hydrochloride of 1,3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate. The product was filtered off, dried and recrystallized from isopropanol.

Yield: 25.67f (7a2%). Melting point: 208-21
0℃. The other physical values of this product corresponded to those described in Example 1.

Example 5 4-chlorophenoxyacetic acid 1a66f (0.1 mol) was dissolved in isopropanol 40-. 1゜6-screw (
dimethylamine)-2-chloropropane 16.702(
A solution of impropatur (cL 1 mol) was added dropwise at 5-10°C. The reaction mixture was heated to boiling for 2 hours, cooled,
200 ml of diethyl ether was added and the hydrochloride of 1,6-pis(dimethylamino)-2-propyl-4-chlorophenoxyacetate was precipitated by introducing gaseous hydrogen chloride. The product was taken apart and washed with ether. Yield: 31.2F (80,5910). Melting point = 208-21
0℃. The other physical values of this product corresponded to the haze described in Example 1.

Example 6 (4-
chlorophenoxy)-sodium acetate 20.86 f
The procedure was as in Example 5, except that a solution of (0.1 mol) was used. The dihydrochloride thus obtained (yield - Jl:
30,629.85%) was the same as that obtained in Example 1.

, Example 7 Methyl-4-chlorophenoxyacetate 10.0f (
0.05 mol) and 1,3-bis(dimethylamino)-2
A mixture of -propa/-Lua, 55 f (0.05 mol), 1.9 t of sodium ethoxide, and 30 - of benzene is boiled for 10 hours, and the resulting methanol is used as an azeotrope formed with benzene. The reaction mixture was continuously distilled off. The residual solution was evaporated in vacuo, the residue was dissolved in a 10:1 mixture of diethyl ether and acetone,
The hydrochloride of 11,3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate was precipitated by introducing gaseous hydrogen chloride. The crude product was taken from house to house and recrystallized from Improper Tools. Yield: 14.80t (7'6
．． 5 wheels). Melting point: 207-210°C. The other physical values of the product were the same as described in Example 1.

Example 8 Tablets containing 250 μ of active ingredient and having the following composition were prepared.

The following margin ingredients Quantity Ki/tablet Active ingredients 250 Lactose 45 Crystalline cellulose 17 Tar 5 Paraffin oil 8 Crystalline active acid content 2500F, anhydrous lactose 450F and anhydrous crystalline cellulose 170F were mixed in a homogenizer with 8 tons of paraffin oil and Anhydrous isopropanol 35
Homogenized with 0-. The mass thus obtained was filtered and passed through a sieve to dry the granules. The dried material was homogenized with Talc 502 and the mixture was pressed into tablets weighing 325q using a conventional tablet press.

Example 9 Enteric solvent capsules or dragees were prepared by coating the product obtained in Example 8 with an enteric solvent layer by methods known per se.

Example 10 Capsules having the following composition were prepared.

Ingredients Quantity/Capsule Active Ingredient 250 Known Auxiliaries Sufficient amount of active ingredient was homogenized with additives and packed into hard gelatin capsules.

Example 11 Powdered capsules containing 250 or 500+l IP of active ingredient were prepared. Active ingredient 250 capes or 500q
were each packed into powder ampoules. The contents of these ampoules should be diluted 10” with distilled water before use.

Claims (1)

[Scope of Claims] 1. 1,6-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate represented by formula (1) and physiologically acceptable acid addition salts thereof. 2.1.3-bis(dimethylamino)-2-propyl-
The compound according to claim 2K1, which is 4-chlorophenoxyacetate dihydrochloride. (5) When producing 1,3-bis(dimethylamino)-2-propyl-4-chlorophenoxyacetate represented by formula (1) and its physiologically acceptable acid addition salt, the general formula (10 (wherein B1 is a carboxyl group, a cyano group, an alkoxycarbonyl group, a halogenocarbonyl group, a 4-chlorophenoxyacetoxycarbonyl group, or a group represented by the general formula -000MCl,
Me■ is an alkali metal or ammonium ion)
A compound represented by the following formula is reacted with a compound represented by the general formula (1[D (in the formula, R is a hydroxy group or a merogen atom), and optionally,
1,3-bis(dimethylamino)-2-propyl-4- represented by the above formula (1), which comprises separating the obtained compound represented by formula (1) from the reaction mixture in the form of an acid addition salt. Process for the preparation of chlorophenoxy acetate and its physiologically acceptable acid addition salts. 4. Claim f which separates the acid addition salt in the form of hydrochloride
The method described in item 43. 5, (4-chlorophenoxy)acetyl chloride and 1
．． A process according to any one of claims 3 and 4, wherein 3-bis(dimethylamino)-2-propanol is used as starting material. 6. 1,3-bis(dimethylamino)-2- represented by formula (1)
A pharmaceutical composition comprising propyl-4-chlorophenoxyacetate, or a physiologically acceptable acid addition salt thereof, as the active ingredient, in admixture with a suitable inert pharmaceutical carrier.